The zinc dyshomeostasis hypothesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated pro...

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Autores principales:	Travis J A Craddock, Jack A Tuszynski, Deepak Chopra, Noel Casey, Lee E Goldstein, Stuart R Hameroff, Rudolph E Tanzi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a6a1505ff3ab47df974d9d8ec7d38513
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spelling	oai:doaj.org-article:a6a1505ff3ab47df974d9d8ec7d385132021-11-18T07:24:25ZThe zinc dyshomeostasis hypothesis of Alzheimer's disease.1932-620310.1371/journal.pone.0033552https://doaj.org/article/a6a1505ff3ab47df974d9d8ec7d385132012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22457776/?tool=EBIhttps://doaj.org/toc/1932-6203Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.Travis J A CraddockJack A TuszynskiDeepak ChopraNoel CaseyLee E GoldsteinStuart R HameroffRudolph E TanziPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e33552 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Travis J A Craddock Jack A Tuszynski Deepak Chopra Noel Casey Lee E Goldstein Stuart R Hameroff Rudolph E Tanzi The zinc dyshomeostasis hypothesis of Alzheimer's disease.
description	Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.
format	article
author	Travis J A Craddock Jack A Tuszynski Deepak Chopra Noel Casey Lee E Goldstein Stuart R Hameroff Rudolph E Tanzi
author_facet	Travis J A Craddock Jack A Tuszynski Deepak Chopra Noel Casey Lee E Goldstein Stuart R Hameroff Rudolph E Tanzi
author_sort	Travis J A Craddock
title	The zinc dyshomeostasis hypothesis of Alzheimer's disease.
title_short	The zinc dyshomeostasis hypothesis of Alzheimer's disease.
title_full	The zinc dyshomeostasis hypothesis of Alzheimer's disease.
title_fullStr	The zinc dyshomeostasis hypothesis of Alzheimer's disease.
title_full_unstemmed	The zinc dyshomeostasis hypothesis of Alzheimer's disease.
title_sort	zinc dyshomeostasis hypothesis of alzheimer's disease.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/a6a1505ff3ab47df974d9d8ec7d38513
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The zinc dyshomeostasis hypothesis of Alzheimer's disease.

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